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Literature review | BY BIONASSAY

The Art of Repair

Bovine Milk Secretome as a Repair Ritual
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Introduction

Abstract

Bovine milk secretome—the ensemble of growth factors, cytokines, peptides, and extracellular vesicles (EVs) including exosomes—constitutes a multifactorial signaling system with emerging applications in dermatology. This review synthesizes current evidence on composition, mechanisms, formulation strategies, and integrative clinical use. We highlight opportunities (e.g., ECM remodeling, barrier repair), challenges (e.g., delivery, stability, sourcing, regulatory clarity), and practical considerations for clinical adoption. Evidence to date is promising; standardization of isolation, dosing, and clinical endpoints remains a priority.¹,⁴,⁶,¹¹

Table of contents

  1. 1 Introduction: Why Secretome Matters
  2. 2 How Secretome Works: Mechanisms & Science
  3. 3 Formulation and Delivery Considerations
  4. 4 Synergistic Use with Other Modalities
  5. 5 Frequently Asked Questions (FAQ)
  6. 6 Concluding Thoughts
  7. 7 References

  • 1.1 What is the Secretome?

  • 1.2. Why the Secretome (vs. Individual Peptides)?

The secretome refers to the complete set of bioactive molecules secreted by cells into their extracellular environment—growth factors, cytokines, chemokines, peptides, and extracellular vesicles (EVs) such as exosomes—that coordinate intercellular communication and tissue remodeling.

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Rather than acting in isolation, these factors form an integrated signaling network orchestrating wound healing, inflammation control, and extracellular matrix (ECM) turnover.¹,² In bovine milk, this signaling system is adapted for neonatal development and includes immunomodulatory proteins and vesicle-encapsulated nucleic acids that promote growth, immune defense, and cellular resilience—features of interest for regenerative dermatology.³,⁴

Cosmetic peptides target specific pathways (e.g., matrikines for collagen stimulation), but typically act one channel at a time.⁵

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The secretome, by contrast, delivers multichannel biosignaling: growth factors for repair and renewal, cytokines for immune balance, and EVs/exosomes that carry proteins and microRNAs to fine-tune gene expression. This systems-level approach better mirrors the skin’s innate repair language.¹–⁴

bionassay-peptide

  • The secretome is basically all the “substances” that cells naturally release to communicate with each other and help tissues stay healthy or repair themselves.

    Think of each cell like a tiny factory that sends out packages filled with useful materials - like messages, tools, and ingredients - to help other cells do their jobs. 

1.3 Challenges and Considerations

Transforming bovine milk secretome into an effective and safe skincare ingredient is a sophisticated process that requires scientific precision, ethical sourcing, and expert formulation design.
1

DELIVERY

Many secretome components (proteins, EVs) are fragile and degrade without protection. Encapsulation (liposomes), hydrogels, and biocellulose scaffolds can protect vesicles, meter release, and improve skin residence.¹,³,⁴
2

STABILITY

Bioactivity can be compromised by temperature, light, and pH; cold-chain, lyophilization, and stabilizing carriers are common strategies.⁵
3

SOURCING

Animal health, lactation stage, and processing affect proteomic/vesicular profiles; standardized collection and characterization are essential.⁶
4

REGULATORY

EV-based products sit between biologics, cosmetics, and nutraceuticals; transparent labeling, safety testing, and alignment with evolving guidance are critical.⁷,⁸

2.1. Components of the Secretome

The bovine milk secretome is a sophisticated ensemble of bioactive messengers—including growth factors, cytokines, exosomes, and other extracellular vesicles—that together orchestrate cellular communication, repair, and regeneration. These components act synergistically to restore skin balance, enhance extracellular matrix (ECM) integrity, and promote long-term resilience.
GROWTH FACTORS
CYTOKINES
EXOSOMES

Growth Factors

(Such as TGF-β) Regulate proliferation, collagen synthesis, ECM remodeling, angiogenesis, and scar modulation.¹,²

Cytokines & Chemokines

Fine-tune immune responses and help resolve excessive inflammation, maintaining skin’s natural equilibrium.¹⁴ Note: Growth factors and cytokines overlap but are not synonymous; TGF-β bridges both functional families.¹⁶

Exosomes & EVs

Nano-vesicles transporting proteins, lipids, and nucleic acids (e.g., microRNAs) that reprogram recipient cells.¹⁷

2.2. Mechanisms of Action

The regenerative efficacy of the bovine milk secretome is mediated through a series of interrelated biosignaling pathways that coordinate repair, immune balance, and matrix renewal.

BIOSIGNALING AND COMMUNICATION
Secretome-derived ligands interact with cellular receptors to activate intracellular signaling cascades, including SMAD, MAPK, and PI3K/AKT pathways. These pathways regulate transcriptional programs responsible for keratinocyte proliferation, fibroblast activation, and immune modulation, ultimately restoring cutaneous homeostasis.⁷

ANTI-APOPTOTIC ACTIVITY
Growth factors such as IGF-1 and FGF-2 promote cell survival by inhibiting stress-induced apoptosis, preserving the integrity of dermal and epidermal structures during injury or oxidative stress.¹³,¹⁹

ANTI-INFLAMMATORY AND IMMUNOMODULATORY EFFECTS
Cytokines including IL-10 and IL-1 receptor antagonist (IL-1ra) temper excessive inflammatory responses while maintaining essential immune surveillance, creating a controlled environment conducive to tissue repair.¹⁴

EXTRACELLULAR MATRIX (ECM) REMODELING
Growth factors and extracellular vesicle cargo stimulate fibroblasts to synthesize collagen, elastin, and hyaluronic acid, supporting structural regeneration, improved elasticity, and sustained skin resilience.

2.3. Biosignaling: The Language of the Secretome

Biosignaling is the fundamental mechanism through which the secretome communicates with skin cells, coordinating repair and regeneration at the molecular level. Growth factors and cytokines initiate this process by binding to specific membrane receptors—such as tyrosine kinase or serine/threonine kinase receptors—triggering intracellular cascades including MAPK/ERK, PI3K/AKT, and SMAD pathways. These signaling routes regulate the transcription of genes involved in proliferation, extracellular matrix synthesis, angiogenesis, and inflammation control.¹,¹⁴

Exosomes and extracellular vesicles complement this system by delivering bioactive cargo—most notably microRNAs (miRNAs)—that fine-tune gene expression post-transcriptionally within recipient cells.¹⁷,¹⁸ This dual mechanism ensures precision: while growth factors and cytokines act as “on-switches” initiating cellular responses, exosomal miRNAs serve as modulators, refining the magnitude and duration of these effects.

The outcome of this synchronized biosignaling network is a harmonized regenerative response across skin cell populations—fibroblasts increase collagen and elastin synthesis, keratinocytes promote barrier renewal, and immune cells regulate inflammation. In essence, the secretome does not simply stimulate repair; it restores the biological dialogue that maintains skin homeostasis and structural integrity.

  • Biosignaling is like a domino effect happening inside your skin cells. It’s the way the secretome communicates - sending signals that tell cells when to repair, renew, or calm inflammation.

2.4. What the Literature Shows

Current literature highlights the multifaceted regenerative potential of the bovine milk secretome, demonstrating consistent biological effects across preclinical and early clinical studies.

WOUND HEALING

Extracellular vesicles (EVs) derived from bovine milk have been shown to accelerate wound closure, enhance re-epithelialization, and modulate scar formation through coordinated activation of fibroblasts and angiogenic pathways.⁸

ANTI-AGING AND DERMAL REGENERATION

Secretome-enriched and milk EV–based formulations have demonstrated improvements in skin hydration, elasticity, and collagen organization, suggesting a capacity to restore structural integrity and dermal resilience.¹,⁴,³⁵

INFLAMMATION AND OXIDATVE STRESS

Exosomal microRNAs and cytokine components within the secretome exert antioxidant and immunomodulatory effects, reducing oxidative stress and restoring immune homeostasis in inflammatory skin models.¹⁴,³¹

bionassay-inflammation-skin

3.0. Formulation and Delivery Considerations

Harvest, Purification, and Concentration

Preparation of the bovine milk secretome begins with pretreatment processes such as acidification, renneting, or citrate treatment, followed by skimming, defatting, and microfiltration to remove casein micelles and lipids prior to extracellular vesicle (EV) and protein capture.²⁰–²² The core isolation workflow commonly employs differential ultracentrifugation, with or without density gradients, while alternative approaches such as size-exclusion chromatography (SEC) or polymer precipitation can increase yield but may introduce contaminants.²³–²⁶ Gradient-based purification enhances vesicle purity and morphology. EV identity and composition are verified through canonical markers (CD9, CD81) and RNA profiling of miRNA and mRNA cargo.²⁷ Persistent challenges include co-precipitation of casein and fat, where pretreatment parameters and isolation methods significantly influence purity and reproducibility.²⁸,²⁹

Stabilization and Preservation of Bioactivity

Maintaining the biological integrity of secretome-derived factors requires stabilization strategies that protect against enzymatic degradation, oxidation, and denaturation. Liposomal encapsulation offers enhanced stability, protection from proteolysis, and improved dermal deposition, while hydrogel matrices provide controlled release and biocompatibility with the skin.²⁶,³⁰–³³ Hybrid systems such as liposomes-in-hydrogel combine occlusive hydration with sustained diffusion of bioactive molecules. Notably, milk-derived EVs inherently serve as natural carriers, preserving the functional activity of their protein and RNA cargo.²⁶

Dosing and Concentration Control

Standardization of dosing remains essential for reproducibility and safety. Quantification methods include particle counts via nanoparticle tracking analysis (NTA), total protein concentration, or sentinel marker expression.³¹ Functional potency should be validated through bioassays assessing fibroblast migration, collagen synthesis, and cytokine modulation. Given the nonlinear nature of growth factor and cytokine signaling, excessive concentrations may provoke fibrosis or irritation; therefore, gradual dose escalation is advised.²⁶

Penetration and Targeting

The stratum corneum represents a significant barrier to macromolecular transport. Strategies to enhance delivery include occlusion and hydration, incorporation into liposomal or EV-based carriers, and hydrogel or biocellulose mask systems that increase residence time and skin permeability.³²,³³ Target engagement focuses primarily on keratinocytes, for barrier reinforcement, and fibroblasts, for extracellular matrix (ECM) remodeling. EVs and liposomes facilitate endocytic uptake while protecting labile cargo during transit.³⁴

Scaffolds and Carrier Systems

Advanced delivery architectures can further optimize performance. Liposomes-in-hydrogel systems provide immediate hydration with controlled diffusion, while biocellulose sheets offer high water content and intimate skin contact, ideal for delivering fragile secretome components.³²,³³ Upstream process aids such as microfiltration, ceramic membrane filtration, and cold-chain processing improve purity, extend shelf life, and preserve bioactivity throughout manufacturing.²¹

4.0. Synergistic Use with Other Modalities

Bovine milk secretome complements procedures/topicals by supplying multi-signal inputs (growth factors, cytokines, miRNAs) that support repair and matrix remodeling.³⁵

MICRONEEDLING

Immediate post-needling application may amplify fibroblast signaling and accelerate repair; sequence: cleanse → microneedle → secretome serum/gel → optional occlusive mask.³⁵

PRF/PRP

Adds signaling diversity (miRNAs/cytokines) to autologous growth factors; typical flow: microneedling and PRP/PRF in-session → topical secretome for 0–72h → 1–2 weeks.³⁶

RETINOIDS

Secretome may buffer irritation and aid barrier recovery; pause strong retinoids 24–48h pre-procedure; resume 48–72h post, layering secretome first.³⁶

PEPTIDES

Combine single-pathway peptides with multifactorial secretome; apply secretome serums before peptide creams.

SCAFFOLDS

Hydrogels/biocellulose improve secretome residence and uptake; secretome-infused matrices can outperform EVs alone in wound models.³⁷

SAFETY NOTES

The bovine milk secretome, has demonstrated notable stability and regenerative potential in preclinical models—particularly in UV-damaged skin, where it supports cellular repair, collagen renewal, and antimicrobial defense.³¹ This complex biological mixture requires precise formulation to preserve its delicate bioactive components. Delivery systems such as liposomes, hydrogels, and biocellulose matrices are essential for maintaining stability, controlling release, and optimizing skin absorption.³²

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Although current research indicates that bovine milk secretome is biocompatible and well tolerated, rare inflammatory responses reported with unrelated exosome-based applications underscore the importance of strict source quality, purification accuracy, and dosing control. To ensure reproducibility and safety, the field must continue advancing toward standardized protocols for secretome isolation, compositional profiling, and dosing parameters—critical steps for achieving consistency in both research and clinical applications.

5.0. Frequently Asked Questions (FAQ)

When will results be visible?

Hydration/calmness/glow often within 1–2 weeks; structural changes (firmness, texture, fine lines) typically 8–12 weeks.
Is bovine milk secretome safe?

Generally biocompatible and well tolerated; outcomes depend on purity/ source/ processing. Use products with rigorous safety and stability testing. Caution in dairy allergy/highly reactive skin.
Can it be combined with other treatments?

Yes—particularly with microneedling /PRF /PRP (healing window), retinoids /exfoliants (buffer irritation), and peptides/antioxidants (broader signaling). Apply secretome first.
Who benefits most?

Compromised/stressed skin, intrinsic/extrinsic aging, dry/barrier-impaired skin, and reactive skin requiring immune balance.
What to look for in a product/provider?

Transparent sourcing, validated composition (proteomics/EV analysis), stabilizing delivery (hydrogels/liposomes/biocellulose), safety testing, and clinical backing.

6.0. Concluding Thoughts & Recommendations

PROMISE
The bovine milk secretome represents a multifactorial, physiology-mimetic approach to skin regeneration, capable of addressing extracellular matrix (ECM) remodeling, immune modulation, and barrier repair in a single, harmonized process. Its complex signaling network mirrors endogenous communication pathways, offering potential advantages over single-molecule actives by restoring balance rather than forcing isolated effects.

CAVEATS
Despite its promise, key challenges remain. Variability in molecular composition due to sourcing and processing, sensitivity to environmental and formulation factors, and the evolving regulatory landscape underscore the need for standardization. Furthermore, while preclinical and pilot clinical findings are encouraging, large-scale, controlled human trials are still limited and required to fully validate efficacy and safety profiles.

ROADMAP
A gradual, evidence-based integration strategy is recommended. Begin with a well-formulated serum or mask used in the evening to support nocturnal repair, then layer with moisturizers and daily sun protection. Strong actives such as retinoids or exfoliants should be staggered to prevent overstimulation. Procedural synergy can be leveraged post-microneedling, PRF, PRP, or resurfacing, when skin permeability and biosignal receptivity are heightened. Consistent use over 8–12 weeks typically aligns with visible structural improvements in elasticity, texture, and tone.

SAFETY CONSIDERATIONS
Individuals with dairy allergies or highly reactive skin should consult a dermatologist prior to use. Secretome-based treatments should complement—not replace—medical care. As with any emerging biotechnology, outcomes may vary depending on individual skin biology, adherence, and procedural context.

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